GPRC5A: A retinoic acid–inducible GPCR involved in epithelial homeostasis and tumor biology

Gene Information: G protein-coupled receptor class C group 5 member A (GPRC5A), also known as retinoic acid–inducible protein 3 (RAI3), is a protein-coding gene located on chromosome 12p13. It belongs to the class C orphan GPCR family. GPRC5A expression is transcriptionally regulated by retinoic acid and is implicated in epithelial cell differentiation and tissue homeostasis.

Protein Expression: GPRC5A is predominantly expressed in epithelial tissues, especially in lung epithelium, where it shows relatively high basal expression. It is also detected in tissues such as kidney, pancreas, and gastrointestinal tract. Its expression is often dysregulated in cancers, particularly lung cancer.

Signaling Pathway: GPRC5A has been reported to modulate multiple signaling pathways, including: NF-κB signaling (inflammation regulation) ; STAT3 signaling (tumor progression and survival) ; EGFR-related pathways (cell proliferation and differentiation). Functionally, GPRC5A is considered a tumor suppressor in lung tissue, where its loss promotes inflammation-associated tumorigenesis.

Therapeutic Relevance: Although no approved drugs directly target GPRC5A, its role in cancer biology—especially in non-small cell lung cancer (NSCLC)—makes it a potential biomarker and therapeutic target.

• Exons 2–4 of the mouse Gprc5a gene that encode the entire protein (from ATG to stop codon), including 3’UTR are replaced with the corresponding human sequences in B-hGPRC5A mice.
• The endogenous mouse promoter and 5′ UTR regions are retained, allowing human GPRC5A expression to be driven by the native mouse Gprc5a promoter, while endogenous mouse Gprc5a transcription and translation are abolished.

Strain specific analysis of GPRC5A mRNA expression in wild-type C57BL/6N mice and B-hGPRC5A Mice by RT-PCR. Small intestine RNA was isolated from wild-type C57BL/6N mice (+/+) and homozygous B-hGPRC5A mice (H/H), and then cDNA libraries were synthesized by reverse transcription, followed by PCR with human GPRC5A primers. Human GPRC5A mRNA was exclusively detectable in homozygous B-hGPRC5A mice  mice but not in wild-type mice.